title: Effect of tumor necrosis factor-alpha on estrogen metabolism and endometrial cells: potential physiological and pathological relevance.
abstract: BACKGROUND
  Estrogen and its metabolites play a critical role in the pathophysiology of the endometrium. The bioavailability of estrogen and estrogen metabolites in endometrial tissues depends on the expression of enzymes involved in estrogen biosynthesis and metabolism. Substantial evidence indicates that estrogen-dependent endometrial disorders are also associated with proinflammatory milieu. However, the mechanism whereby inflammation contributes to these conditions is not known.
  
  
  OBJECTIVE
  The objective of the study was to investigate the effect of TNF-alpha on estrogen metabolism and the expression of estrogen-metabolizing genes in human endometrial glandular epithelial cells (EM1).
  
  
  METHODS
  EM1 were treated with 17beta-estradiol (E2) with or without TNF-alpha. Capillary liquid chromatography-tandem mass spectrometry analysis was used for quantitative measurement of estrogens and estrogen metabolites. Western blot analysis, reporter gene assay, and real-time RT-PCR were used to assess the expression of estrogen-metabolizing genes.
  
  
  RESULTS
  TNF-alpha treatment significantly increased the level of total estrogen and estrogen metabolites and significantly increased the rate of conversion of estrone (E1) into E2. TNF-alpha also enhanced the oxidative metabolism of estrogen into catecholestrogens with concomitant inhibition of their conversion into methoxyestrogens. Gene expression analysis revealed that TNF-alpha induced the expression of genes involved in E2 biosynthesis (steroidogenic factor-1 and aromatase) and activation (17beta- hydroxysteroid dehydrogenase type 1 and cytochrome P-450, 1B1) with simultaneous repression of genes involved in estrogen inactivation (17beta-hydroxysteroid dehydrogenase type 2; catechol O-methyltransferase; and nicotinamide adenine dinucleotide phosphate-quinone oxidoreductase 1).
  
  
  CONCLUSIONS
  TNF-alpha increases the local estrogen biosynthesis in human endometrial glandular cells and directs estrogen metabolism into more hormonally active and carcinogenic metabolites. These effects may impact many physiological and pathological processes that occur within the endometrium.
authors.affiliation: Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Texas Medical Branch at Galveston, 300 University Boulevard, Galveston, Texas 77555, USA. sasalama@utmb.edu
authors.forename: Salama A
authors.initials: SA
authors.lastname: Salama
authors.forename: Marwa W
authors.initials: MW
authors.lastname: Kamel
authors.forename: Concepcion R
authors.initials: CR
authors.lastname: Diaz-Arrastia
authors.forename: Xia
authors.initials: X
authors.lastname: Xu
authors.forename: Timothy D
authors.initials: TD
authors.lastname: Veenstra
authors.forename: Sana
authors.initials: S
authors.lastname: Salih
authors.forename: Shaleen K
authors.initials: SK
authors.lastname: Botting
authors.forename: Raj
authors.initials: R
authors.lastname: Kumar
mesh_terms: D001141:Aromatase / Q000235:genetics; D001189:Aryl Hydrocarbon Hydroxylases; D002394:Catechol O-Methyltransferase / Q000235:genetics; D002460:Cell Line; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics; D065633:Cytochrome P-450 CYP1B1; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics; D004717:Endometrium / Q000166:cytology / Q000378:metabolism*; D004958:Estradiol / Q000494:pharmacology; D004960:Estradiol Dehydrogenases / Q000235:genetics; D004967:Estrogens / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000235:genetics; D054339:Steroidogenic Factor 1 / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
chemical_list: D004967:Estrogens; C515057:NR5A1 protein, human; D054339:Steroidogenic Factor 1; D014409:Tumor Necrosis Factor-alpha; D004958:Estradiol; D003577:Cytochrome P-450 Enzyme System; D004960:Estradiol Dehydrogenases; C513331:HSD17B1 protein, human; C523763:HSD17B2 protein, human; D001141:Aromatase; D001189:Aryl Hydrocarbon Hydroxylases; C585496:CYP1B1 protein, human; D019363:Cytochrome P-450 CYP1A1; D065633:Cytochrome P-450 CYP1B1; D016660:NAD(P)H Dehydrogenase (Quinone); C447479:NQO1 protein, human; D002394:Catechol O-Methyltransferase